Single-Domain Antibody-Based TCR-Like CAR-T: A Potential Cancer Therapy

Zhu, Linghua; Yang, Xiaomei; Zhong, Dani; Xie, Shenxia; Shi, Wei; Li, Yangzi; Hou, Xiaoqiong; HuaYao,; Zhou, Huihui; Zhao, Minlong; Ding, Ziqiang; Zhao, Xiangxuan; Mo, Fengzhen; Yin, Shutao; Liu, Aiqun; Lü, Xiaoling

doi:10.1155/2020/2454907

Cited by 10 publications

(8 citation statements)

References 101 publications

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“…Some guidelines to fine-tune TCR mimic antibodies to increase their affinity have been described that may help improve the sensitivity of mTCR CAR T cells. 52 , 53 Second, concerns of on-target/off-tumor and off-target toxicities may limit this approach, as such toxicities were observed in affinity-matured TCR T-cell therapy against MAGE-A3. To prevent these toxicities in patients, a systematic screening system for cross-reactivity of PRAME mTCR CAR T cells should be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia

et al. 2023

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Preferentially Expressed Antigen in Melanoma (PRAME) , a cancer testes antigen provides an ideal target for immunotherapy in AML. We have shown expression of PRAME in a significant subset of childhood and adult AML and lack of expression in normal hematopoiesis. Although an intracellular antigen, we developed a novel approach to target PRAME using a CAR construct encoding a targeting domain based on T cell receptor (TCR) mimic antibodies that targets the peptide:HLA complex. We used the antibody sequence from a previously designed antibody, Pr20, a TCR mimic antibody that recognizes PRAME ALY peptide in complex with HLA-A*02 and verified expression of PRAME in AML cell lines and primary AML blasts. Using the Pr20 antibody sequence, we developed CAR T cells (PRAME mTCRCAR T) to be tested against primary AML patient samples and AML cell lines that express the PRAME antigen in the context of HLA-A2 expression. In contrast to the appropriate controls, PRAME mTCRCAR T cells demonstrate target specific and HLA-mediated in vitro activity in OCI-AML2 and THP-1 cell lines, HLA-A2 cell lines expressing the PRAME antigen, and against primary AML patient samples. In vivo cell-derived xenograft models treated with PRAME mTCRCAR T cells demonstrated potent leukemia clearance and improved survival compared to unmodified T-cell controls. Furthermore, the cytolytic activity of PRAME mTCRCAR T cells was enhanced by treating the target cells with IFN-γ, which increases PRAME antigen expression. These results demonstrate the feasibility and efficacy of targeting PRAME with novel PRAME mTCRCAR T cells.

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Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia

et al. 2023

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“…Most notably, De Munter et al designed a TCR-like nanobody CAR-T therapeutic with two tandem TCR-like nanobodies bispecific to HER2 and CD20 to activate T cells and kill tumor cells [13]. Subsequently, other studies combined a TCR-like nanobody CAR-T with nanobodies targeting immune checkpoint inhibitors to address the tumor microenvironment to enhance the persistence of CAR-T cells and suppress tumor growth [15][16][17]. These approaches provide compelling options to improve the nanobody-based antigen binding domain in CARs that are directed to the MHC complex with the specificity of TCR and increased affinity to CARs [18].…”

Section: Car-t Cells and Nanobodiesmentioning

confidence: 99%

Emerging Novel Combined CAR-T Cell Therapies

Nguyễn

Johanning²,

Shi

2022

Cancers

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Chimeric antigen receptors (CAR) T cells are T cells engineered to express membrane receptors with high specificity to recognize specific target antigens presented by cancer cells and are co-stimulated with intracellular signals to increase the T cell response. CAR-T cell therapy is emerging as a novel therapeutic approach to improve T cell specificity that will lead to advances in precision medicine. CAR-T cells have had impressive outcomes in hematological malignancies. However, there continue to be significant limitations of these therapeutic responses in targeting solid malignancies such as heterogeneous antigens in solid tumors, tumor immunosuppressive microenvironment, risk of on-target/off-tumor, infiltrating CAR-T cells, immunosuppressive checkpoint molecules, and cytokines. This review paper summarizes recent approaches and innovations through combination therapies of CAR-T cells and other immunotherapy or small molecule drugs to counter the above disadvantages to potentiate the activity of CAR-T cells.

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“…As more and more TCR and TCRL mAb structures emerge, machine learning ( 99 ) may offer more guidance on TCRL engineering. Last, for use in physiologic conditions, protein scaffolds other than mAbs sometimes possess better properties including protein stability, reduced immunogenicity, and increased tissue penetration ( 90 , 100 ). Lessons learned from TCRL mAb development can be applied to alternative protein scaffolds ( 90 ) to expand TCRL methodology.…”

Section: Future Directionsmentioning

confidence: 99%

TCR-like antibodies targeting autoantigen-mhc complexes: a mini-review

2022

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T cell receptors (TCRs) recognize peptide antigens bound to major histocompatibility complex (MHC) molecules (p/MHC) that are expressed on cell surfaces; while B cell-derived antibodies (Abs) recognize soluble or cell surface native antigens of various types (proteins, carbohydrates, etc.). Immune surveillance by T and B cells thus inspects almost all formats of antigens to mount adaptive immune responses against cancer cells, infectious organisms and other foreign insults, while maintaining tolerance to self-tissues. With contributions from environmental triggers, the development of autoimmune disease is thought to be due to the expression of MHC risk alleles by antigen-presenting cells (APCs) presenting self-antigen (autoantigen), breaking through self-tolerance and activating autoreactive T cells, which orchestrate downstream pathologic events. Investigating and treating autoimmune diseases have been challenging, both because of the intrinsic complexity of these diseases and the need for tools targeting T cell epitopes (autoantigen-MHC). Naturally occurring TCRs with relatively low (micromolar) affinities to p/MHC are suboptimal for autoantigen-MHC targeting, whereas the use of engineered TCRs and their derivatives (e.g., TCR multimers and TCR-engineered T cells) are limited by unpredictable cross-reactivity. As Abs generally have nanomolar affinity, recent advances in engineering TCR-like (TCRL) Abs promise advantages over their TCR counterparts for autoantigen-MHC targeting. Here, we compare the p/MHC binding by TCRs and TCRL Abs, review the strategies for generation of TCRL Abs, highlight their application for identification of autoantigen-presenting APCs, and discuss future directions and limitations of TCRL Abs as immunotherapy for autoimmune diseases.

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Single-Domain Antibody-Based TCR-Like CAR-T: A Potential Cancer Therapy

Cited by 10 publications

References 101 publications

Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia

Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia

Emerging Novel Combined CAR-T Cell Therapies

TCR-like antibodies targeting autoantigen-mhc complexes: a mini-review

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